ENPP2 (ectonucleotide pyrophosphatase/phosphodiesterase 2)

2007-02-01   Mary L. Stracke , Timothy Clair 

Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bldg 10, Rm 2A33, MSC 1500, 9000 Rockville Pike, Bethesda, MD 20892

Identity

HGNC
LOCATION
8q24.12
LOCUSID
ALIAS
ATX,ATX-X,AUTOTAXIN,LysoPLD,NPP2,PD-IALPHA,PDNP2
FUSION GENES

DNA/RNA

Note

mRNA length 3276 or 3120 bp, depending upon alternate splicing.
Atlas Image
ENPP2 Gene: Intron-exon organization of ENPP2.

Description

The ENPP2 gene is 81,754 bp in length and is composed of 26 exons. Part of exon 1 and 26 are untranslated (UTR); translation extends from the remainder of exon 1 through the proximal portion of exon 26; however, there is a 152 bp exon (exon 12) that is alternatively spliced and is included primarily in neurally derived tissues.

Transcription

The mRNA for ENPP2 is 3276 bp with exon 12 and 3120 bp without it. The ENPP2 promoter is reported to have four SP1 sites as well as binding sites for NFAT and NF-kappaB but no TATA or CAAT boxes. The only transcription factor that has been proven to increase ENPP2 protein expression is NFATC2/NFAT1, after release of alpha6beta4 from hemidesmosomes in a breast cancer cell line. A number of growth factors have been found to stimulate ENPP2 protein expression, while several inflammatory cytokines have been reported to inhibit expression.

Pseudogene

CYCSP23

Proteins

Atlas Image
ENPP2 Protein (NPP2/ATX): Organization of domains and other critical elements within ENPP2.

Description

The ENPP2 protein, NPP2 or ATX, is an N-glycolsylated member of the ecto-nucleotide pyrophosphatase and phosphodiesterase (NPP) family of proteins. The NPP2 precursor contains 915 amino acids, 105.2 KDa; and an alternately spliced variant is 863 amino acids, 99.0 KDa. The amino terminal signal peptide sequence is cleaved at a signal peptidase site between G27 and F28 to yield a secreted protein that contains 888/836 amino acids, 102.3/96.9 KDa. NPP2 contains up to 3 ASN-linked glycosylation sites that appear to be required for secretion as well as for stabilization of its active conformation.

Expression

NPP2 is expressed in many tissues during development, but it is critical for blood vessel maturation and neurogenesis. Certain inflammatory cytokines and the tumor suppressor CST6 downregulate ENPP2 expression, and some of the NPP2 products exert a negative feedback on its expression. Conversely, a number of growth factors as well as EBV infection (in Hodgkins lymphoma) upregulate ENPP2 expression. Disruption of hemidesmosomes in breast cancer cells releases alpha6beta4, which initiates a signaling cascade that culminates in the activation of the transcription factor NFAT1, which binds to the ENPP2 promoter to upregulate protein expression. Upregulation of ENPP2 has been reported in a number of aggressive tumors, including glioblastoma, undifferentiated anaplastic thyroid carcinoma, invasive breast carcinoma, and metastatic hepatocellular carcinoma.
In adults, NPP2 is the major source of serum and plasma lysophospholipase D activity. It is also highly expressed in brain, kidney, liver, ovary, small intestine, and placenta, and is present in many other tissues.

Function

NPP2 is a Type 2 nucleotide pyrophosphatase and phosphodiesterase that also has ATPase activity. In addition, NPP2 is the major source of serum and plasma lysophospholipase D activity, hydrolyzing lysophosphatidylcholine into lysophosphatidic acid as well as cyclic phosphatidic acid. NPP2 also hydrolyzes sphingosylphosphorylcholine into sphingosine-1-phosphate; however, NPP2 is not a major source of sphingosine-1-phosphate in plasma. The production of lysophosphatidic acid is thought to account for many of the physiological and pathological roles of ENPP2.
Both enzymatic activities of NPP2 share a common catalytic domain. Like other members of the NPP family, NPP2 is a metallo-enzyme with binding sites for 2 metal atoms coordinated by three critical histidines (H316, H360, and H475) and associated aspartates (D172, D312, and D359). T210 is nucleotidylated during the nucleotide pyrophosphatase/phosphodiesterase reaction and is essential for hydrolysis of substrate during the lysophospholipase D reaction as well.

Homology

NPP2 is a member of the nucleotide pyrophosphatase and phosphodiesterase family, which includes ENPP1 (PC1) and ENPP3 (B10). Although the catalytic domain is highly conserved within this family of proteins, only NPP2 possesses lysophospholipase D activity.

Mutations

Note

There are a number of single nucleotide polymorphisms (SNPs) that have been reported within the ENPP2 gene but none are yet reported to be associated with altered phenotype. However, knockout of ENPP2 is lethal in mice (approximately E12), therefore mutations associated with loss of function might be lethal.

Implicated in

Entity name
Various cancers
Disease
Overexpression of the ENPP2 protein has been associated with tumor cell motility and invasion, tumor growth and metastasis, and blood vessel formation.
Prognosis
ENPP2 is over-expressed in poorly differentiated non-small cell lung carcinomas and invasive and metastatic hepatocellular carcinoma. In thyroid carcinomas, ENPP2 expression was found to be higher in undifferentiated anaplastic thyroid carcinoma cell lines and tissues than in follicular thyroid carcinomas or goiters. When glioblastoma multiforme cells were collected from tumor cores vs. areas of white matter invasion, ENPP2 was found to be overexpressed predominantly at the invasive front.
Oncogenesis
Upregulation of NPP2 expression appears to be associated with cancer progression rather than with oncogenesis. Transfection of ENPP2 cDNA into mouse fibroblast cell lines (NIH3T3 clone7) did not result in tumorigenic cell lines, but transfection into Ras-transformed fibroblasts resulted in rapidly growing, hematogenous, highly metastatic tumors. NPP2 expression was found in Hodgkins lymphoma cells as well as in CD30+ anaplastic large-cell lymphomas. In the Hodgkins lymphomas , EBV infection was correlated to induction of ENPP2 expression (P = 0.006).
Transfection of the tumor suppressor CST6 into MDA-MB-435 cells resulted in down-regulation of ENPP2. In contrast, down regulation of ENPP2 by specific siRNAs resulted in down-regulation of the tumor suppressors, thrombospondin-1 and thrombospondin-2 (THBS1 and THBS2, respectively).
Entity name
Diabetes
Disease
NPP2 expression is highly upregulated during adipocyte differentiation and its product, lysophosphatidic acid, stimulates proliferation in preadipocytes. In genetically obese, diabetic mice, NPP2 expression was increased in adipose tissue compared to their lean siblings. This is a possible model for type 2 diabetes, which has a strong genetic component.

Bibliography

Pubmed IDLast YearTitleAuthors
104731251999Developmental expression analysis of murine autotaxin (ATX).Bächner D et al
159330522005Induction of autotaxin by the Epstein-Barr virus promotes the growth and survival of Hodgkin lymphoma cells.Baumforth KR et al
146914472004Microarray analysis identifies Autotaxin, a tumour cell motility and angiogenic factor with lysophospholipase D activity, as a specific target of cell transformation by v-Jun.Black EJ et al
157001352005Potential involvement of adipocyte insulin resistance in obesity-associated up-regulation of adipocyte lysophospholipase D/autotaxin expression.Boucher J et al
152589142004Lipid phosphate phosphatases and related proteins: signaling functions in development, cell division, and cancer.Brindley DN et al
158978782005Integrin alpha6beta4 promotes expression of autotaxin/ENPP2 autocrine motility factor in breast carcinoma cells.Chen M et al
145003802003Autotaxin hydrolyzes sphingosylphosphorylcholine to produce the regulator of migration, sphingosine-1-phosphate.Clair T et al
89953941997Autotaxin is an exoenzyme possessing 5'-nucleotide phosphodiesterase/ATP pyrophosphatase and ATPase activities.Clair T et al
159304942005Footer: a quantitative comparative genomics method for efficient recognition of cis-regulatory elements.Corcoran DL et al
126425762003Autotaxin is released from adipocytes, catalyzes lysophosphatidic acid synthesis, and activates preadipocyte proliferation. Up-regulated expression with adipocyte differentiation and obesity.Ferry G et al
128376322003Phosphodiesterase-Ialpha/autotaxin: a counteradhesive protein expressed by oligodendrocytes during onset of myelination.Fox MA et al
126338532003The hydrolysis of lysophospholipids and nucleotides by autotaxin (NPP2) involves a single catalytic site.Gijsbers R et al
147448552004Lysophosphatidic acid and autotaxin stimulate cell motility of neoplastic and non-neoplastic cells through LPA1.Hama K et al
91928341997Expression and transcriptional regulation of the PD-Ialpha/autotaxin gene in neuroblastoma.Kawagoe H et al
150271162004Expression, regulation and function of autotaxin in thyroid carcinomas.Kehlen A et al
127278172003Site-directed mutations in the tumor-associated cytokine, autotaxin, eliminate nucleotide phosphodiesterase, lysophospholipase D, and motogenic activities.Koh E et al
164360502006The N-terminal hydrophobic sequence of autotaxin (ENPP2) functions as a signal peptide.Koike S et al
119432092002Autotaxin promotes motility via G protein-coupled phosphoinositide 3-kinase gamma in human melanoma cells.Lee HY et al
87986971996Stimulation of tumor cell motility linked to phosphodiesterase catalytic site of autotaxin.Lee HY et al
85795791996Cloning, chromosomal localization, and tissue expression of autotaxin from human teratocarcinoma cells.Lee HY et al
170130942006Autotaxin stimulates urokinase-type plasminogen activator expression through phosphoinositide 3-kinase-Akt-nuclear [corrected] factor kappa B signaling cascade in human melanoma cells.Lee J et al
79829641994cDNA cloning of the human tumor motility-stimulating protein, autotaxin, reveals a homology with phosphodiesterases.Murata J et al
115595732001Autotaxin (NPP-2), a metastasis-enhancing motogen, is an angiogenic factor.Nam SW et al
166019222006Identification of large-scale molecular changes of Autotaxin(ENPP2) knock-down by small interfering RNA in breast cancer cells.Noh JH et al
172080432007Secretion and lysophospholipase D activity of autotaxin by adipocytes are controlled by N-glycosylation and signal peptidase.Pradère JP et al
171928092007Autotaxin (NPP-2) in the brain: cell type-specific expression and regulation during development and after neurotrauma.Savaskan NE et al
163564772006The candidate tumor suppressor CST6 alters the gene expression profile of human breast carcinoma cells: down-regulation of the potent mitogenic, motogenic, and angiogenic factor autotaxin.Song J et al
17339491992Identification, purification, and partial sequence analysis of autotaxin, a novel motility-stimulating protein.Stracke ML et al
168295112006Autotaxin stabilizes blood vessels and is required for embryonic vasculature by producing lysophosphatidic acid.Tanaka M et al
121769932002Identification of human plasma lysophospholipase D, a lysophosphatidic acid-producing enzyme, as autotaxin, a multifunctional phosphodiesterase.Tokumura A et al
168374662006Cyclic phosphatidic acid is produced by autotaxin in blood.Tsuda S et al
121193612002Autotaxin has lysophospholipase D activity leading to tumor cell growth and motility by lysophosphatidic acid production.Umezu-Goto M et al
124983892002Expression of autotaxin (NPP-2) is closely linked to invasiveness of breast cancer cells.Yang SY et al
104234041999Autotaxin expression in non-small-cell lung cancer.Yang Y et al
115935321999Expression of autotaxin mRNA in human hepatocellular carcinoma.Zhang G et al
167828872006Autotaxin, a secreted lysophospholipase D, is essential for blood vessel formation during development.van Meeteren LA et al

Other Information

Locus ID:

NCBI: 5168
MIM: 601060
HGNC: 3357
Ensembl: ENSG00000136960

Variants:

dbSNP: 5168
ClinVar: 5168
TCGA: ENSG00000136960
COSMIC: ENPP2

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000136960ENST00000075322Q13822
ENSG00000136960ENST00000259486Q13822
ENSG00000136960ENST00000427067E7EUF1
ENSG00000136960ENST00000518958E5RIB9
ENSG00000136960ENST00000520066E5RJ49
ENSG00000136960ENST00000522167E5RIA2
ENSG00000136960ENST00000522826Q13822

Expression (GTEx)

0
50
100
150
200
250
300
350

Pathways

PathwaySourceExternal ID
Ether lipid metabolismKEGGko00565
Ether lipid metabolismKEGGhsa00565
MetabolismREACTOMER-HSA-1430728
Metabolism of vitamins and cofactorsREACTOMER-HSA-196854
Metabolism of water-soluble vitamins and cofactorsREACTOMER-HSA-196849
Vitamin B5 (pantothenate) metabolismREACTOMER-HSA-199220

Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
121769932002Identification of human plasma lysophospholipase D, a lysophosphatidic acid-producing enzyme, as autotaxin, a multifunctional phosphodiesterase.195
167828872006Autotaxin, a secreted lysophospholipase D, is essential for blood vessel formation during development.188
194774322009Expression of autotaxin and lysophosphatidic acid receptors increases mammary tumorigenesis, invasion, and metastases.168
183272612008Autotaxin, an ectoenzyme that produces lysophosphatidic acid, promotes the entry of lymphocytes into secondary lymphoid organs.94
220027502011Autotaxin and LPA receptor signaling in cancer.86
204950102010Autotaxin--an LPA producing enzyme with diverse functions.67
166274852006Autotaxin is overexpressed in glioblastoma multiforme and contributes to cell motility of glioblastoma by converting lysophosphatidylcholine to lysophosphatidic acid.63
157697512005Inhibition of autotaxin by lysophosphatidic acid and sphingosine 1-phosphate.62
203796142010Personalized smoking cessation: interactions between nicotine dose, dependence and quit-success genotype score.62
227448592012Pulmonary autotaxin expression contributes to the pathogenesis of pulmonary fibrosis.56

Citation

Mary L. Stracke ; Timothy Clair

ENPP2 (ectonucleotide pyrophosphatase/phosphodiesterase 2)

Atlas Genet Cytogenet Oncol Haematol. 2007-02-01

Online version: http://atlasgeneticsoncology.org/gene/40455/enpp2